The purpose of this proposal is to foster the scientific development and laboratory skills of Dr. Claudia R. Morris, MD, in order that she may become an independent clinical investigator. The comprehensive sickle cell center at Children's Hospital Oakland and its Research Institute will provide the applicant with the ideal setting in which to investigate the impact of oral arginine administration on nitric oxide production in sickle cell disease (SCD) at the clinical, biochemical and cellular levels. Through the collaboration with the clinical mentor, Elliott Vichinsky MD, and an extensive network of experienced scientific and clinical researchers, Dr. Morris will obtain the foundation for the development of an independent academic career. Vaso-occlusion is responsible for most of the morbidity in SCD. The etiology of vascular obstruction in SCD is multifactorial, but mechanisms regulating vascular tone are likely to include nitric oxide (NO), as NO is one of the most potent vasodilators known. NO metabolites (NOx) are elevated in SCD patients at baseline, but decrease significantly during vaso-occlusive crisis (VOC) and acute chest syndrome (ACS). L- Arginine (L-Arg) is the precursor to NO, and Dr. Morris has demonstrated that L-Arg levels are also decreased in SCD patients during VOC and ACS. Dr. Morris has also recently demonstrated that oral L- Arg supplementation can increase endogenous NOx levels in SCD patients during VOC, while causing a paradoxical decrease in NOx levels when administered to SCD patients at steady-state. L-Arg therefore has the potential to alter the nature of VOC in SCD by increasing NO production. The specific aims of the proposal are: (1) to institute a blinded, placebo control, phase Il/Ill clinical trial in SCD patients hospitalized with VOC to determine if oral L-Arg therapy will decrease the length of hospitalization, and (2) to characterize some of the biochemical and cellular effects of arginine therapy in SCD patients with VOC. The outcome of this proposal may impact both patient care and clinical assessment. It offers greater insight into the pathophysiology of SCD, and is the foundation for future studies. Dr. Morris has demonstrated that an L-Arg deficiency may be involve in some of the vaso-occlusive complications of SCD, hence L-Arg supplementation may be a new therapeutic intervention that will improve quality of life for patients with SCD.